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Papers of the Week

2021 Feb 05

Toxicol Sci

Torsadogenic action of cisapride, dl-sotalol, bepridil and verapamil analyzed by the chronic atrioventricular block cynomolgus monkeys: Comparison with that reported in the CiPA in silico mechanistic model.


Goto A, Sakamoto K, Kambayashi R, Nunoi Y, Izumi-Nakaseko H, Kawai S, Takei Y, Matsumoto A, Kanda Y, Sugiyama A
Toxicol Sci. 2021 Feb 05.
PMID: 33544870.


In order to bridge the gap of information between the in silico model and human subjects, we evaluated torsadogenic risk of cisapride, dl-sotalol, bepridil and verapamil selected from 12 training compounds in the comprehensive in vitro proarrhythmia assay (CiPA) using the chronic atrioventricular block monkeys. Cisapride (0, 1 and 5 mg/kg, n=5 for each dose), dl-sotalol (0, 1, 3 and 10 mg/kg, n=5 for each dose), bepridil (0, 10 and 100 mg/kg, n=4 for each dose), verapamil (0, 1.5, 15 and 75 mg/kg, n=4 for each dose) were orally administered to the monkeys in conscious state. Five mg/kg of cisapride, 1, 3 and 10 mg/kg of dl-sotalol and 100 mg/kg of bepridil prolonged ΔΔQTcF, which was not observed by verapamil. Torsade de pointes was induced by 5 mg/kg of cisapride in 2 out of 5 animals, by 10 mg/kg of dl-sotalol in 5 out of 5 and by 100 mg/kg of bepridil in 2 out of 4, which was not induced by verapamil. These torsadogenic doses were normalized by their maximum clinical daily ones to estimate torsadogenic risk. The order of risk was dl-sotalol > bepridil ≥ cisapride > verapamil in our study. Since the order was bepridil ≥ dl-sotalol > cispride > verapamil in CiPA in silico mechanistic model validation, sympathetic regulation on the heart may play a pivotal role in the onset of torsade de pointes in vivo.